Considerable forces are exerted on the fetal head as it dilates the cervix and pelvic structures during parturition. Because of the compliant fetal skull, these forces can cause intracranial pressure (ICP) to greatly exceed amniotic fluid pressure, thereby decreasing cerebral perfusion pressure. Thus, cerebral blood flow (CBF) could decrease. Mechanisms to preserve CBF are likely to be critical to the fetus during labor. Because fetal brain vessels appear to have a limited ability to dilate when perfusion pressure is reduced, we reasoned that the fetus would rely heavily on increasing arterial pressure to sustain CBF and evoke the classic Cushing response. When ICP was elevated, we found that fetal lambs could generate a remarkable 33% increase in arterial pressure without curtailing placental blood flow. More surprising is that this pressor response is more effective in preserving CBF and cerebral O2 uptake in fetal lambs than in postnatal lambs and sheep. The overall goal of this proposal is to investigate the mechanisms involved in this pressor response in fetal lambs. First, we will investigate the fetal circulatory response to elevated ICP under conditions which would occur during labor. We will determine if external compression of the fetal head generates a profound pressor response that sustains cerebral perfusion as effectively as is the case when ICP is increased by infusion of cerebrospinal fluid. Furthermore, we will determine the dynamic aspects of the pressor response during repetitive, intermittent increases in ICP. Next, we will identify neurohumoral effector mechanisms. We will test whether the vasopressin and angiotensin systems are augmenting sympathoadrenal activation to produce the massive peripheral vasoconstrictor response in the fetus. In postnatal animals, we have observed selective regional vasodilation. We will determine if this vasodilation is due to the maturational development of a beta adrenergic mechanism. Finally, we will test the idea that the fetus more vigorously defends against reductions of CBF because the brain operates in an intrauterine environment that is relatively more hypoxic and hypercapnic than postnatal conditions. These studies are important for understanding the mechanisms of how the fetus copes with the stress of head compression in the process of normal labor and delivery. It is perhaps not coincidental that preliminary data show the most potent Cushing response is in fetus. The protection afforded by a Cushing response is likely to be especially important to the human fetus with its relatively large head and cranium.